ProjectSummary Germcellsundergoextensiveepigeneticreprogrammingduringdevelopment.Duringthiscriticalperiod, retrotransposonsarereactivatedduetogenome-wideerasureofDNAmethylationandarere-silencedbyde novoDNAmethylation.Retrotransposons,mainlyLINEs,SINEs,andendogenousretroviruses(collectively referredtoasjunkDNA),occupy40%ofthemammaliangenome.Althoughretrotransposonsplayan importantroleingenomeevolution,theirmobilizationcouldbedetrimentaltogenomeintegrity.Multiple epigeneticmechanismsareresponsibleforsilencingretrotransposonsinthegermline:DNAmethylation, repressivehistonemodification,smallRNAs,andheterochromatinization.Giventheextremeabundanceofthe retrotransposonsandtheparamountimportanceofgermlinegenomeintegrity,novelmechanismsfor retrotransposonsilencingmayexist.Insupport,wehavefoundthatTEX15,agermcell-specific3059-aa proteinwithanewlyidentifiedfunctionaldomain,isrequiredformeiosisandmalefertility,andisanovel epigeneticregulatoressentialforretrotransposonsilencing.Basedonthesedata,wehypothesizethatTEX15 isanovelgermcell-specificregulatorofretrotransposonactivationandthatmeioticcollapseisthe ultimate?fail-safe?mechanismforpreventingtransmissionofmalegermcellsinwhich retrotransposonsareinordinatelyactivated.Inthisproject,wewill1)determinetheTEX15-mediated epigeneticlandscapeduringmalegermcelldevelopmentinmouseusinggenomicapproaches,2)elucidate molecularmechanismsunderlyingTEX15function,and3)screenforretrotransposonactivationandutilize wholeexomesequencingtoidentifygeneticmutationsthatcompromiseepigeneticsilencingof retrotransposonsintestisbiopsiesfromazoospermicmen.Together,thesestudieswillidentifynovelfactorsin thesilencingofretrotransposonsandprovideessentialinsightsintotheetiologyofmaleinfertilityinhumans.